The mortal rate caused by liver disease in Korea has reached to very high level, i.e., about 23.5 per 100000 (male: 37.8, female: 9.0), which is principle pathology resulting in death of middle-aged Korean. Especially, an alcoholic liver disease is mainly caused by chronic over-drinking. The alcoholic liver diseases include fatty liver, chronic hepatitis, acute hepatitis, liver cirrhosis, and liver cancer, especially, the alcoholic fatty liver is a mild and early-stage liver disease induced by excess consumption of ethanol. Because it was generally considered to be benign and reversible, there is no standard method for the treatment of the disease. However, it is now being recognized that fatty liver, if not treated properly, leads to steatohepatitis, fibrosis and ultimately end-stage liver disease.
The etiology of alcoholic liver disease has not yet fully identified till now. Alcohol affects on the transcription activity of various transcription factors, which has been reported to cause to the metabolic disorder of fatty acid. Specifically, various genes involved in lipid oxidation are controlled by particular transcription factors, especially, PPAR-alpha involved in lipid oxidation and SREBP-1 (sterol response element binding protein 1) involved in lipogenesis (Laura E. Nagy: Molecular aspects of alcohol metabolism; Transcription factors involved in early ethanol-induced liver injury, Annu. Rev. Nutr. 24:55-78, 2004). PPAR-alpha plays important roles in lipid oxidation in liver and forms complex-dimer with RXR-alpha when it is activated by ligands, resulting in inducing the expression of various genes (Reddy JK: Nonalcoholic steatosis and steatohepatitis. II. Peroxisomal beta-oxidation, PPAR-alpha and steatohepatitis, AM. J. Physiol. Gastrointest. Liver Physiol., 281:G1333-29, 2001). However, alcohol inhibits the activity of transcription factors such as PPAR-alpha and then inhibits the lipolysis resulting in the formation of fatty liver. Therefore, the increase of the PPAR-alpha activity increases lipid oxidation and prevents from the formation of fatty liver. For example, 4-week's administration of alcohol into mice decreased the transcription activity of PPAR-alpha resulting in the formation of fatty liver however the co-treatment with PPAR-alpha activator did not form the fatty liver (Fisher M et al., Peroxisome proliferator-activated receptor agonist treatment reverse PPAR-alpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice, J. Biol., Chem., 278, pp. 27997-8004, 2004).
SREBP-1 (sterol response element binding protein 1) is a crucial factor controlling the several gens involved in triglyceride formation and the increased activity of the transcription of SREBP-1 stimulated the lipogenesis resulting in fatty liver. Alcohol increases the expression of SREBP-1, which causes the various genes involved in lipid biosynthesis resulting in the increase of lipid synthesis. Accordingly, the decrease of SPEBP-1 expression could prevent from the formation of fatty liver. For example, it has been observed that the fatty liver induced by alcohol feeding was significantly reduced in the transgenic mouse defected with SREBP-1 expression (Cheng Ji et al; Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model, Journal of Hepatology, 45:717-724, 2006).
Accordingly, the increase of transcription activity of PPAR-alpha controlling the synthesis of enzyme involved in lipid oxidation and inhibition of transcription activity of SREBP-1 involved in lipogenesis could efficiently prevent from the alcoholic fatty liver.
However, there has been not reported or disclosed about the therapeutic effect of serine on liver diseases in any of above cited literatures, the disclosures of which are incorporated herein by reference.
Therefore, the present inventors have endeavored to find the effective agent for treating liver diseases and found that the serine inhibits the SREBP-1 transcription activity involved in lipid synthesis and reduced the fatty liver formation through various in vitro test such as the inhibition effect on lipid accumulation caused by alcohol in H4IIEC3 cell as well as inhibition effect on SREBP1 activation and in vivo test such as the inhibition effect on the fatty liver formation, triglyceride accumulation, lipid metabolism indicators, ALT activity, and triglyceride level in acute and chronic fatty liver induced mouse model fed by alcohol.